Oral Submucous Fibrosis

The aetiology of OSMF is multifactorial. 

• Areca or betel nut is the name for the nut derived from the Areca plant. 
• A dose dependent relationship for both frequency and duration of chewing has been noted in the development of OSMF. 
• Areca, betel or paan chewing is a common recreational habit in the Indian subcontinent and its consumption is becoming increasingly more common in Western communities due to migration. 
• Certain preparations of Areca nut include tobacco and other known carcinogens. Areca nut in isolation is a recognized carcinogen, as it contains certain tannins and alkaloids, which have a cytotoxicity and genotoxicity. Slaked lime, which is another common ingredient in Areca nut preparations has elevated concentrations of arsenic. 
• In the Hindu religion, Areca nut is believed to be divine and it is consumed due to the perceived medicinal value. It has also been perceived as an aphrodisiac, an agent that improves oral hygiene and reduces halitosis, a salivary stimulant that improves digestion and, within the Indian subcontinent, it is believed to have a stabilizing effect on glycemic control in patients with diabetes. 
• Arecoline, a byproduct after metabolism of Areca nut, is an alkaloid that readily crosses the blood brain barrier and has been implicated in the addictive potential of the Areca nut chewing habit. The subsequent physiological effects are often described as euphoric, users also describe heightened awareness and improved productivity. 
• Areca nut chewing has been implicated as the aetiological factor in the development of OSMF. The International Agency for Research on Cancer has categorized Areca nut as a Group 1 carcinogen.

• Other aetiological factors reported include a pre-existing tobacco use habit (smokeless), haematinic deficiencies, anaemia and malnutrition. 
• There may also be a genetic predisposition, with association with certain HLA subtypes and haplotypes (A10/DR3).  
• Malnutrition, anaemia and haematinic deficiencies are associated with atrophy of the oral mucosa and increased potential for collagen synthesis. 

Areca nut chewing is the main aetiological risk factor in the development of OSMF and the above factors may be viewed as contributory.

• OSMF is characterised by abnormal collagen deposition. 
• Areca alkaloids, such as arecoline, cause fibroblast proliferation. Flavourings within areca nut preparations, such as tannins, may also inhibit collagenase activity. 
• The progression of the disease is associated with replacement of the easily degradable type 1 collagen, with more resistant type 3 collagen. There is also inhibition of collagen phagocytosis. 

• Histopathological specimens will exhibit certain features of OSMF, such as atrophy or thinning of the epithelium and juxtaepithelial hyalinization and collagen of varying density, along with a fibrosed lamina propria and anchoring fibrils.

OSMF occurs predominantly in the Indian subcontinent and South East Asia including India, Taiwan, China, Bangladesh, Malaysia, Singapore, Thailand and Sri Lanka. It has also been reported in South Africa and Saudi Arabia. OSMF is found in Asian populations in the USA, United Kingdom and developed countries and therefore the condition exhibits a global health burden. The number of global cases in 1996 was estimated to be 2.5 million. The prevalence in India has been reported to be as high as 30%. Consumption of Areca nut globally has been reported to be as high as 5-20%. OSMF symptoms tend to develop in the 4^th -5th decade of life, but cases have been reported in the patients as young as eleven. The disease has a female preponderance for unknown reasons.

• OSMF has been clinically categorized into four stages by More (2012), encompassing an eruptive and then fibrotic phase. 
• The eruptive phase may be associated with vesicle formation, with burning sensation and discomfort in the oral cavity being common. The texture of the oral mucosa begins to change, losing its suppleness. Pallor of the mucosa progresses, and the mucosa begins to blanch. Mucosal petechia may develop, as well as melanotic mucosal pigmentation, mucosal ulceration and erythematous areas. 
• In stage two, fibrosis occurs in the vesicles and ulcers when they heal. Vertical and circular palpable fibrous bands in the buccal mucosa and/or oropharynx develop with or without stomatitis. Thinner bands may be present in the earlier stages when compared to these palpable bands.
• In stage three, palpable fibrous bands may be present in any part of the oral cavity with or without stomatitis. Stage four encompasses all of the above with the development of a potentially malignant disorder or frank oral squamous cell carcinoma.
• Specific findings in stages two to four include trismus, depigmentation of the gingiva, atrophic uvula and depapillation of the tongue. Changes in facial aesthetics may also be observed with sinking of the cheeks which does not correlate to age or nutritional status. 
• In severe cases, speech and hearing deficits may develop. OSMF has been reported to have a significant impact on quality of life in the later stages. 
• More also described a functional staging of OSMF based on interincisal mouth opening; Stage 1 (greater than or equal to 35 mm), stage 2 (between 25 and 35 mm), stage 3 (15 and 25mm) and stage 4 (less than 15mm).

• Paymaster in 1956 first reported the premaligant potential of the condition. 
• There are significant geographical variations in the reported malignant transformation rates. The rate is generally higher in India, when compared to other countries. 
• A potential explanation of this is the way areca nut is prepared with additional additives. Taiwanese studies found that tobacco products are generally not used in conjunction with areca nut products and this could account for the lower rate of malignant transformation in this population. 
• The rate of malignant transformation has been estimated to be between 1 and 9%.
• A higher malignant transformation rate has been observed in those with a concurrent oral leukoplakia. 
• Oral cancers originating from OSMF have also been reported to be both less and more aggressive when compared to Oral Cancer originating from other lesions within the oral cavity. 

In the early stages, OSMF may be misdiagnosed. Patients complaining of a burning sensation with mucosal atrophy may be diagnosed with Oral Dysaesthesia, with or without an underlying contributing factor such as a haematinic deficiency or anaemia. Careful history taking and enquiry into recreational habits is fundamental. OSMF may present with features similar to other oral potentially malignant disorders, such as oral lichen planus.

Scleroderma is an autoimmune condition affecting the skin, internal organs and blood vessels. It is characterised by diffuse sclerosis of the skin and other connective tissue. Scleroderma may present with fibrous bands in the oral mucosa and progressive trismus. Patients with scleroderma will also have extraoral complaints. Microvascular imaging, testing for autoantibodies help establish the diagnosis of scleroderma.

Amyloidosis is characterised by the deposition of amyloid proteins (fibrillar protein) in tissues. Systemic amyloidosis may present with macroglossia or progressive trismus. Careful history taking, blood and biopsy help establish the diagnosis.

In its later stages, OSMF may present as frank oral SCC, leukoplakia and erythroplakia.

• Careful enquiry into recreational habits will strongly suggest a diagnosis of OSMF. As OSMF is a potentially malignant condition, incisional biopsies are necessary.
• Histopathological analysis is helpful in clinical staging of the disease, in which the distribution and number of fibroblasts, collagen fibers, presence and number of inflammatory cells and blood vessels are correlated with the disease staging. 
• Trauma from the biopsy procedure induces a degree of fibrosis which can contribute to worsening trismus. 
• Certain biomarkers, such as mRNA,can influence the staging of disease and genetic analysis of specimens may predict future malignant transformation. 
• Hematoxylin and eosin is the most common stain used in the diagnosis of OSMF.

Patients should be counselled on the continued use of Areca nut chewing and its role in the aetiopathogenesis and risk of malignant transformation and should be encouraged to stop the habit. OSMF carries a significant global disease burden and primary prevention is a key focus of government strategy in countries within the Indian subcontinent. Approaches such as banning Areca plant products and their preparations, as well as education on the harmful effects of Areca nut chewing have been demonstrated to be useful in primary prevention at both individual and population levels. OSMF often presents late creating a management dilemma. 

OSMF is chronic, progressive condition that results in fibrosis of the oropharyngeal mucosa and, occasionally, the upper oesophagus, as a result of physiologic changes induced by Areca nut chewing. Areca nut and its metabolites are carcinogenic and various preparations of Areca nut include other carcinogens. The malignant transformation rate varies geographically and has been ranges from 1-9%. The rate of malignant transformation is dose dependent and correlated with the duration and intensity of Areca nut chewing habit and when used in combination with alcohol and tobacco consumption. There is no universally accepted management protocol. 

Globally, knowledge of the condition amongst the general population and healthcare professionals is low. This may contribute to the late presentation of these patients. All healthcare professionals have a role in the primary prevention and recognition of the disease.

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